Aliphatic-aromatic amine and process of making same



Patented June 25, 1935 A I I v I ,I

UNITED. STATES ,PA'T-ENT OFFICE surname-momma AMINE m moo- ESS or mxmo sun:

Karl Wilhelm Rosenmund and Fritz Kills, Kiel,

No Drawing. Application February 8, 1933, Serial v No. 655,762. In Germany 51211127, 1931 9 Claims. (01. 280-127) Our invention relates to the production of new great number of compounds belonging to this chemical compounds designed for use in the therclass, amongst others the following:

apeutical treatment of certain ailments; and more lsp y y i especially to tertiary amines of; thealiphatic-aro- 5 matic series, which may be substituted for papav- T 5 erine in all the uses to which this well known 3H] a remedy is put. he 18 18mm 8 As is well known to those skilled in the art, Bis p ny thy any papaverine is dispensed nowadays in an ever inl0 creasing degree but its use is hampered by cer- H; l0

tain unpleasant secondary efiects, which render Phenefihylmnemsomorwbmethmamme it desirable to replace the papaverine by other C H CH CH 1% CH CH O H o srr- I I compounds having the same beneficiary efiect, but lacking these unpleasant properties. 11; Hi We have now found that in order to obtain t l- 13mm)ethyl-phenylethyl-pm- 15 the beneficiary effect of papaverine it is not necpylamme essary that an isoquinoline nucleus be present, and that compounds which contain the typical phenyl radicals of the papaverine without hav- 7 0B6 1B1 ing undergone condensation into an isoquinoline- 5 0-methoxy-phenethyl-phenethyl-8thylam1n8 20 nucleus, are superior in some respects to the pa- H 'paverine.

OCH;- 6. Bis-(3,4-dimethoxy-phenethyl)methylamine OCH: A A: v

n m I CH: 7. Beta methoxy beta-phenethyl-phenethyl-- onto methylamine 80 I CtHs-CBKOCHt)-CH1NCH:CH2COH5 so CHSO N I l H: Papmim 8. Gamma-phenylpropyl-benzyl-methylamine C6Hl-CHr-CH:CHlN-CHr-COHl 85 5 85 OCH: OH I 9. Bis(gamma-phenylpropy1) -ethylamine o.m-om-om-mh-n-cm-om-omoan- 0 I I I 10. Delta-phenyl-butyl-benzyl-methylamine We have further found that it is not necessary have shown that while the eflects obtained with 45 either, in order to obtain the typical papaverine the different compounds vary to a certain deefiect, that both phenyl radicals present in the gree, they are substantially the same. papaverine be substituted by alkoxy groups, but All these numerous compounds exert a checkthat the peculiar effect of the papaverine is obing influence on the non-striated muscles and tained also if none or only one oxygen-containing are capable of abolishing spasms of the 'nongroup is present in the molecule. striated muscles.- In this respect these com- The length of the carbon chain linking the pounds have proved to be superior to the pa phenylradical to the nitrogen is of no avail as paverine. I e a far as the eiifect'is concerned. The new compounds according to this inven- 55 Careful investigations into the properties of a tion can be obtained by any of the methods serving for producing tertiary amines. In the examples given below as illustrative of this in vention some of these methods have been described by way of example.

In practising our invention we may for instance proceed as follows:

Example 1.

Bis-phenethylethyl amine 14 grams phenylethylchloride are heated 24 hours to 120 C. in a sealed tube together with 15 grams of a 33% alcoholic ethylamine solution and 5.6 grams soda. The solution is then acidulated by adding some hydrochloric acid.-

of 5% and the alcohol and the non-basic fractions are driven off with steam. The residual watery solution is made strongly alkaline with caustic potash solution and extracted with ether.

0n fractionating the etheric solution the com-' pound to be produced is obtained as a basic oil boiling under 8 mm. mercury column at 188 to 190 C. The hydrochloride forming white needles melts at 137 C.; it readily dissolves in water, but only with dificulty in ethylacetate.

pressure at 109 C. is obtained, the yield being 85% 01 the calculated yield. Inorder to convert the compound into the tertiary base, 10 grams. are heated 24 hours to 120 C. in a sealed tube together with an equal quantity of phenylethylchloride under addition of 30 com. alcohol and 20 com. of a 20% caustic soda solution. The reaction mixture on being treated as described with reference to Example 1 results in 17 grams bis-phenylethyl-allylamine, an oil boiling under 4 mm. pressure at 182 C. The hydrochloride forming white needles melting at 119-120 C., dissolves readily in Water, but is insoluble in ether.

Example 3 Phenethyl phenisoproply-methylamine:

13 grams phenylethylamine and 14 grams benzylmethylketone are dissolved in 50 com. alcohol and hydrogenated in the presence of 3 grams tate.

Example 4 (Alpha, beta-diphen) .ethyl-phenylethyl-propylamine:

5 grams phenylethylamine and 8 grams benzylphenylketone are heated 30 minutes to 120 C. The resultant product is dissolved in 50 ccm. alcohol and into the boiling solution are entered 5 grams sodium metal.v When the development of hydrogen has come to an end, ccm. water are added for dilution and the liquor is acidulated with hydrochloric acid of 25%, whereby the hydrochloride of (alpha, beta-diphen)ethyl-phenylethylamine, melting at 261 C. is separated out. To convert this compound to the tertiary base 5 grams of the hydrochloride are heated 12 hours to C. in a sealed tube with 4 grams soda, 50 ccm. alcohol of 50% and 2.5 grams propylbromide. When the reaction has come to an end the alcohol is removed by evaporation, the watery residue rendered alkaline with caustic potash solution and extracted with ether. By adding to the extract an alcoholic solution of hydrochloric acid up to acid reaction, the hydrochloride of the new compound is separated out, 60% of the calculated quantity being recovered. The compound forms. white needles melting at 263 C. and dissolving in water only with dificulty.

Example 5 O-methoxy-phenethyl phenethyl ethylamine 3 grams o-methoxy-phenethylamine and 3 grams phenylacetaldehyde are dissolved in 30 com. alcohol and subjected to catalytic hydrogenation as described with reference to Example 3. The o-methoxy-phenethyl-phenethylamine thus obtained can be converted into a hydrochloride, which is moderately soluble in water and melts at 142 C., the yield being 4 grams. 6 grams of the basic compound are heated 24 hours to 100 C. in a sealed tube with 4 grams ethylbromide, 2 grams soda and 40 ccms. alcohol of 50%. By treating the resulting product further as described with reference to Example 1, the compound to be produced is obtained under the form of a basic oil, the hydrochloride of which forms white needles melting at C. and dissolving only moderately in water, more readily in alcohol. The yield is 4.5 grams.

Example 6 of a 5% palladium-barium sulfate catalyst obtained by reducing a solution of palladious chloride with formaldehyde in the presence of barium sulfate and soda (see Houben-Weyl Methoden der organischen Chemie", 3rd Ed. vol. 2, p. 500). When the absorption of hydrogen has come to an end, the mass is filtered, the alcohol removed by evaporation and the residual phenethyl-phenisopropylamine separated out under the form of the hydrochloride by adding some hydrochloric acid of 25%. The hydrochloride melts at C. In order to convert the compound into the'tertiary base 4 grams of the hydrochloride are heated 3 hours to 140 C. in a sealed tube together with 4 ccm. formaldehyde solution of 35%. After evaporation of the liquid from the reaction product the hydrochloride of phenethyl-phenisopropyl-methylamine remains over. On being recrystallized from ethylacetate to which has been added some ether, the compound is recovered in the form of white needles melting at 124 C. and dissolving readily Bis- (3,4-dimethoxy-phenethyl) methylamine:

5 grams (3,4-dimethoxy-phenethyl) -a.mine are heated with 2 grams of the palladium-barium sulfate catalyst described with reference to Example 3 in the oil bath to about 225 C., while passing hydrogen gas through it, until no further splitting oil? of ammonia can be noticed, which is the case after the lapse of aboutv 1 hour. The residual product is dissolved in hydrochloric acid of 5%, the solution is filtered, caustic alkali in excess is added and the base extracted with ether and precipitated from the etheric solution by adding alcoholic hydrochloric acid until an acid reaction is obtained. The hydrochloride crystallizes from alcohol under the form of white needles melting at 199 C. and dissolving in water only with difilculty. To convert it into the tertiary base, 4 grams of the hydrochloride thus obtained are heated in a sealed tube to 120 C.

in water, but only with difilculty in ethylace- 4 grams formic acid. By adding caustic alkali to water, but insoluble in benzene.

the solutionuntil an alkaline reaction is Ob-Q tained, the tertiary base is precipitated as an oil which quickly solidifies. The hydrochloride melts at 242 C., the yield is 70% of the calculated yield. It forms white needles which dissolve rather readily in alcohol, but only with great dif-' flcultyin ethylacetate. I I

Example 7.

Beta methoxy-beta phenethyl phenethylmethylamine:

3.2 grams beta-methoxy-beta-phenylethylaminc and 3 grams phenylacetaldehyde are dissolved in 30 com. alcohol and subjected to catalytic hydrogenation as described with reference to Example 3. On distillation of the resulting solution there is obtained the beta-methoxy-phen- Example 8 Gamma-phenyl-propylbenzyl-methylamine 1/20 mol. benzybmethylamine are heated -15 hours in a sealed tube to 120 C. with 1/20 m'ol. phenylpropylchloride, 1/20 mol. soda and 50 com. alcohol of 50%. After evaporation of the alc'bhol the residue .is rendered strongly alkaline and extracted with ether, to the etheric solution is added alcoholic hydrochloric acid of until the solution shows an acid reaction and the hydrochloride of the new compound is thus precipitated under the form of an oil, which gradually crystallizes, forming white needles meltingat 146 C. and dissolving in water, but being insoluble in ether. The yield is 75% of the calculated yield.

Example 9 Bisgamma-phenyl-propyl) -ethylamine:

1/20 mol. bisflgamma-phenylpropyl) amine, 1/20 mol. ethylbromide and.1/20 mol. soda are heatedtogetherwith 50 com. alcohol of 50% to 120 C. in a sealed tube. The resulting product is treated further as described with reference to Example 8. One thus obtains the hydrochloride of the new compound which does not crystallize and is soluble in water, but dissolves only with difficulty in ethylacetate. The yield is 70%. Its perchlorate melts at 70 C.

Example 10 Delta-phenyl-butyl-benzyl -me thylamine 1/20 mol. benzyl-methylamine, 1/20 mol. delta.- phenyl-butyl-chloride, l/20 mol. soda and 50 ccm. alcohol of 50% are treated as described with reference to Example 9. One thus obtains the hydrochloride of the tertiary base forming white needles melting at 113 C., and being soluble in The yield is 65%. v

Various changes may be made in the details disclosed in the foregoing specification without departing from the invention or sacrificing the advantages thereof.

The compounds within the scope of our'invention can be defined by the generic formula Rr-M-Nr-Ar-M wherein R; and R2 represent phenylor alkoxysubstituted phenyl groups, A: and A: represent alkylene chains or phenylor alkyl-substituted alkylene-chains of the lower aliphatic series, and Rs, represents an unsubstituted alphyl group of the lower aliphatic series. By the term alphyl group we mean an alkyl group or an unsaturated hydrocarbon group, such as allyl \for example.

One of the processes of our invention comprises condensing a primary amine of the class consisting of Rl-Al-NIIZ, R2Aa--N Ha and Ra-NH: with a compound selectedfrom a second class consisting of RlAl-x, Rz-Az-X and and Rs-X, under conditions of reaction producing liberation of HX and with formation of a secondary amine of the class consisting of R1-A1-NH-R2'A2,

R1A1NH-Rsand R2Az-NHR3, and condensing the resulting secondary amine with a. compound selected from a class consisting of Rs-X, Rz-Az-X and Ri-Ai-X, respectively, under conditions of reaction producing liberation of HX and with formation of a tertiary amine of the aforesaid generic formula; X being a group, such as halogen, aldehyde, ketone, sulfate or sulfo-acid, capable of uniting with an available hydrogen atom of said amines under said conditions of reaction with liberation of HX.

We claim:--

1. Bis- (gamma phenyl propyl) ethylamine, the hydrochloride of which does not crystallize and is soluble in water, the perchlorate melting at 69 to 70 C. and being diflicultly soluble in water, but readily soluble in acetic acid ester.

2. Bis-phenylethyl-ethylamine, a basic oil boiling under 8 mm. pressure at 188 to 190 C., the hydro-chloride forming white needles melting at 137 C. and readily dissolving in water, but'only with difllculty in ethylacetate. 4

3. Bis (3,4 dimethoxy phenethyl) -methylamine, an oily product, which solidifies quickly, its hydrochloride forming white needles melting at 242 C. and dissolving rather readily in alcohol, but only with great difliculty in ethylacetate.

4. The process of preparing bis-phenethylethylamine which comprises heating a phenylethyl halide with ethylamine.

5. The process of preparing bis-(3,4-dimethoxyphenethyl) methylamine which comprises subjecting 3,4-dimethoxyphenethyl-amine to a catalytic hydrogenation and methylating the resulting product.

6. The process of preparing bis-(gammaphenyl propyl) ethylamine which comprises heating bis-phenyl-propylamine with an ethyl halide.

7. Tertiary amines of the aliphatic-aromatic series having the generic formula wherein R1 and Rz represent phenyl or alkoxysubstituted phenyl groups, A1 and A2 represent alkylene chains or phenylor alkyl-substituted alkylene-chains of the lower aliphatic series, and R3 represents an unsubstituted alphyl group of the lower aliphatic series.

8. In the manufacture of tertiary amines of the aliphatic-aromatic series having the generic formula Ri-- xNAr-Bs with a compound selected from a second class consisting of under conditions of reaction producing liberation of HX and with formation of a secondary amine of the class consisting of and condensing the resulting secondary amine *Witlfa compound selected from a class consisting of Ra-X, R2A2-X and Ri-Ai-X,

respectively, under conditions of reaction producing liberation of HX and with formation of a tertiary amine of the aforesaid generic formula; X being a group capable of uniting with an available hydrogen atom of said amines under'said conditions of reaction with liberation of HX.

aooans 9. In the process of manufacturing tertiary amines of the aliphatic-aromatic series having the generic'formula v Rx-AF-N-As-Ra wherein R1 and R2 represent phenyl or alkoxysubstituted phenyl groups, A1 and A: represent.

alkylene chains or phenylor alkyl-substituted alkylene chains of the lower aliphatic series and R3 represents an unsubstituted alphyl group of the lower aliphatic series; the step which consists of condensing a secondary amine of the class consisting of with a compound selected from the class consisting of Rs-X, ai-ni-x and a1 A1-x,

respectively, under conditions of reaction producing liberation of HX and with formation of a tertiary amine of the aforesaid generic formula; X being a group capable of uniting with the hydrogen atom of the amine group of said secondary amines under said conditions of reaction with liberation of HX.

KARLIIWILHELM ROSENMUND. FRITZ KiiLz. 

